Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly (Thornberry, Chem. Biol., 1998, 5, R97-R103). Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, and certain neurodegenerative disorders (see generally Science, 1998, 281, 1283-1312; Ellis et al., Ann. Rev. Cell. Biol., 1991, 7, 663). Caspase-1, the first identified caspase, is also known as interleukin-1β converting enzyme or “ICE.” Caspase-1 converts precursor interleukin-1β (“pIL-1β”) to the pro-inflammatory active form by specific cleavage of pIL-1β between Asp-116 and Ala-117. Besides caspase-1 there are also eleven other known human caspases which have been classified into families based on their biological function.
A number of useful caspase inhibitors has been reported that contain an aspartic acid aldehyde moiety, which will exist in equilibrium with its cyclic hemiacetal form as shown below: where R2 represents the rest of the caspase inhibitor molecule. Based on the hemiacetal, orally available prodrugs of these inhibitors have been developed having the acetal structure 1, where R1 is alkyl or aralkyl, as exemplified by 2. The ICE inhibitor 2 is a prodrug being developed as a treatment for rheumatoid arthritis (see U.S. Pat. No. 5,716,929). 
A process for the preparation of a peptidic caspase inhibitor prodrug of formula 1 where R1 is benzyl and R2 is the amino acid sequence Ac-Y-V-A has been described by Chapman et al. (Bioorg. Med. Chem. Lett. 1992, 2(6), 613). However, this route has significant disadvantages, especially if one wishes to obtain chiral compounds. For example, the process requires an expensive starting material and chromatographic separation of diastereomers (see discussion in PCT application WO/9903852).
More recently, a shorter process for the preparation of compounds of formula 1 where R1 is ethyl has been described (PCT patent application WO/9903852). The process involves the conjugate addition of an aralkylamine to an alkoxyfuranone 3 to provide diastereomeric compounds 4 as shown below: where R3 is an alkyl group having one to four carbons and R4 is an optionally substituted aryl group. The diastereomers of 4, or their addition salts, are reportedly separable by crystallization. The aralkyl group on the amine may then be removed by hydrogenolysis to liberate 5, a useful synthetic intermediate for preparing caspase inhibitors. One limitation to this approach is in the hydrogenolysis conditions used to remove R3R4CH— when R1 is benzyl. Under such conditions, R1 will also be removed.
It would be desirable to have a synthetic route to aspartic acetal caspase inhibitors, or prodrugs thereof, that is amenable to large-scale and overcomes the aforementioned shortcomings or otherwise improves upon the current methods.